Aop:165

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Status

This is a legacy representation of this AOP. Please see the current version here:

https://aopwiki.org/aops/165


AOP Title

Antiestrogen activity leading to ovarian adenomas and granular cell tumors in the mouse
Short name: Antiestrogens and ovarian adenomas/granular cell tumors

Authors

Cancer AOP Workgroup. National Health and Environmental Effects Research Laboratory, Office of Research and Development, Integrated Systems Toxicology Division, US Environmental Protection Agency, Research Triangle Park, NC. Corresponding author for wiki entry (wood.charles@epa.gov)

Status

Please follow the link to snapshots page to view and create Snapshots of this AOP.

Under development: Do not distribute or cite.

OECD Project 1.29: A catalog of putative AOPs that will enhance the utility of US EPA Toxcast high throughput screening data for hazard identification

This AOP page was last modified on 12/11/2016.

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Abstract

This putative adverse outcome pathway (AOP) outlines potential key events leading to a tumor outcome in standard carcinogenicity models. This information is based largely on modes of action described previously in cited literature sources and is intended as a resource template for AOP development and data organization. Presentation in this Wiki does not indicate EPA acceptance of a particular pathway for a given reference agent, only that the information has been proposed in some manner. In addition, this putative AOP relates to the model species indicated and does not directly address issues of human relevance.

Background (optional)

Summary of the AOP

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Molecular Initiating Event

Molecular Initiating Event Support for Essentiality

Key Events

Event Support for Essentiality
Ovarian E2, Decreased Strong
Estrogen receptor (ER) activity, Suppression Strong
secretion of GnRH from hypothalamus, Increased Strong
secrection of FSH from anterior pituitary, Increased Strong
secretion of LH from anterior pituitary, Increased Strong
ovarian stromal cells, Hyperplasia Strong
ovarian epithelium, Hyperplasia Strong
E2 blood concentrations at hypothalamus, Decrease Strong

Adverse Outcome

Adverse Outcome
ovarian adenomas, Promotion
ovarian granular cell tumors, Promotion

Relationships Among Key Events and the Adverse Outcome

Event Description Triggers Weight of Evidence Quantitative Understanding
Ovarian E2, Decreased Directly Leads to E2 blood concentrations at hypothalamus, Decrease Strong
Estrogen receptor (ER) activity, Suppression Indirectly Leads to E2 blood concentrations at hypothalamus, Decrease Strong
E2 blood concentrations at hypothalamus, Decrease Directly Leads to secretion of GnRH from hypothalamus, Increased Strong
secretion of GnRH from hypothalamus, Increased Directly Leads to secrection of FSH from anterior pituitary, Increased Strong
secretion of GnRH from hypothalamus, Increased Directly Leads to secretion of LH from anterior pituitary, Increased Strong
secrection of FSH from anterior pituitary, Increased Indirectly Leads to ovarian stromal cells, Hyperplasia Moderate
secrection of FSH from anterior pituitary, Increased Indirectly Leads to ovarian epithelium, Hyperplasia Moderate
secretion of LH from anterior pituitary, Increased Indirectly Leads to ovarian stromal cells, Hyperplasia Strong
ovarian epithelium, Hyperplasia Indirectly Leads to ovarian adenomas, Promotion Strong
ovarian stromal cells, Hyperplasia Indirectly Leads to ovarian granular cell tumors, Promotion Strong

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Life Stage Applicability

Life Stage Evidence Links

Taxonomic Applicability

Name Scientific Name Evidence Links
CD-1 mouse Mus musculus Moderate NCBI
F344 rat Rattus norvegicus Strong NCBI

Sex Applicability

Sex Evidence Links
Female Strong

Graphical Representation

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Overall Assessment of the AOP

Domain of Applicability

Life Stage Applicability, Taxonomic Applicability, Sex Applicability
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Essentiality of the Key Events

Molecular Initiating Event Summary, Key Event Summary
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Weight of Evidence Summary

Summary Table
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Quantitative Considerations

Summary Table
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Considerations for Potential Applications of the AOP (optional)

References

1. Capen, C. C. (2004). Mechanisms of hormone-mediated carcinogenesis of the ovary. Toxicologic pathology 32 Suppl 2, 1-5.

2. Cohen, I. R., Sims, M. L., Robbins, M. R., Lakshmanan, M. C., Francis, P. C., and Long, G. G. (2000). The reversible effects of raloxifene on luteinizing hormone levels and ovarian morphology in mice. Reproductive toxicology 14(1), 37-44.

3. Long, G. G., Cohen, I. R., Gries, C. L., Young, J. K., Francis, P. C., and Capen, C. C. (2001). Proliferative lesions of ovarian granulosa cells and reversible hormonal changes induced in rats by a selective estrogen receptor modulator. Toxicologic pathology 29(6), 719-26.